How cells adapt to stress

A study by Australian and US scientists found that cultured cells that were overly stressed by chemicals died, whereas cells exposed to short periods of stress at more manageable levels survived and thrived. The researchers set out to show how the cells decided when enough stress was enough.

Managing stress is linked to a cell’s protein packaging system - the endoplasmic reticulum (ER). The ER mediates the folding and maturation of transmembrane and secreted protein molecules.

Protein folding in this way is critical to cellular function - if disrupted, for example by a higher physiological demand for protein folding, stress and disease can result. Disruption of ER function results in the misfolding of proteins, which accumulate in the ER lumen.

ER stress first activates the unfolded protein response, which helps the cell adapt to stress by expanding the ER’s protein-folding capacity and reducing its biosynthetic load - effectively restoring homeostasis.

If ER stress persists, the unfolded protein response induces apoptotic cell death via activation of the death receptor 5 (DR5).

The researchers observed that the same stressors also briefly promote the decay of DR5 via the unfolded protein response sensor IRE1alpha. IRE1alpha transiently catalyses the breakdown of DR5 mRNA, thus allowing time for adaptation.

The extended accumulation of defective proteins within the cell keeps the death receptor on, but if stress is relieved in good time, levels of the death receptor decay back to normal.

This dual response creates a window in which cells sensing protein folding errors can adapt, instead of automatically committing to cell death.

This study was published in Science.